SCIENTIFIC REPORT. San Raffaele Scientific Institute SCIENTIFIC REPORT San Raffaele Scientific Institute

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1 San Raffaele Scientific Institute Via Olgettina, Milano Tel SCIENTIFIC REPORT 2008 SCIENTIFIC REPORT San Raffaele Scientific Institute

2 S C I E N T I F I C R E P O R T 2008

3 COVER IMAGES top left and right: Unpublished image by Patrizia Rovere-Querini (see Innate immunity and tissue remodelling, page 80) top middle: Unpublished image by Gian Giacomo Consalez (see Developmental neurogenetics Unit, pages 31-32) bottom: 2009 American Society of Hematology Cover image of a coming issue of Blood, 2009 Molteni, R; Lage Crespo, C.; Feigelson, S; Moser, C; Fabbri, M; Grabovsky, V; Krombach, F; Laudanna, C; Alon, R and Pardi, R*?-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation Blood: 2009, May 8 (epub ahead of print) doi: /blood * see Leukocyte biology Unit, page 101 Images 1. and 3. have been taken at the San Raffaele s Advanced Light and Electron Microscopy BioImaging Center (see ALEMBIC, page 160) Some ot the images in this volume has been published in scientific papers: Fig. 1, p. 20: Journal of the National Cancer Institute Fig. 5, p. 45: PLoS One (in press) Fig. 16, p. 120: Current Diabetes Reports Fig. 23, p. 139: Nature Genetics Fig. 26, p. 150: Nucleic Acids Research Edited by the San Raffaele Library Layout by Roberto Cremonesi Printed by Grafiche Parole Nuove, Brugherio

4 INDEX - III INDEX INTRODUCTIONS Introduzione del Presidente Introduction by the President Introduction by the Scientific Director Introduction by the Chief Operating Officer VII IX X XII XVI San Raffaele Scientific Retreat 2008 photo gallery XVIII 3rd International Congress Aortic Surgery and Anesthesia How to do it XX Introduction by the General Director Clinical Area XXII DIVISION OF MOLECULAR ONCOLOGY 1 Introduction by the Directors 5 Research Units Lymphoid malignancies Unit 7 B-cell neoplasia 7 Biology of multiple myeloma 8 Cell activation and signalling 8 Dynamic fluorescence spectroscopy in biomedicine 9 Lymphoid organ development 9 Preclinical models of cancer 10 Tumor microenvironment 11 Immuno-biotherapy of melanoma and solid tumors Unit 11 Cancer gene therapy 12 Functional genomics of cancer Unit 12 Model genetics of membrane trafficking Unit 13 Molecular histology and cell growth Unit 13 Tumor biology and vascular targeting Unit 14 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit 14 Endosonography: diagnostic and therapeutic endoscopic ultrasound 15 Gastrointestinal surgical oncology Unit 15 Head and neck oncology Unit 16 Multidisciplinary group for thoracic surgical oncology 17 Oncogenesis in liver neoplasms Unit 17 Onco-hematology Unit 18 Pancreatic cancer Unit: biology and new therapeutic approaches 18 Clinical lymphoid malignancies 19 Gynecologic oncology 19 Medical oncology Unit - Clinical trials 20 Medical oncology Unit - Phase I and lung cancer clinical trials 20 Urological Research Institute (URI) 21 DIVISION OF NEUROSCIENCE 23 Introduction by the Directors 28 Research Units Neuropsychopharmacology Unit 29 Cell adhesion Unit 30 Cellular and molecular neurobiology Unit 30 Cellular neurophysiology Unit 31 Developmental neurogenetics Unit 31 Neurobiology of learning Unit 32 Proteomics of iron metabolism Unit 33 Molecular genetics of mental retardation Unit 33 Neural degeneration Unit 34 Stem cells and neurogenesis 34

5 IV - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit 35 Eye repair Unit 36 Cognitive neuroscience Unit 36 Experimental neurosurgery Unit 37 Functional neuroradiology Unit 37 In vivo Human molecular and structural neuroimaging Unit 38 Neuroothology Unit 38 Psychiatry and clinical psychobiology 39 Sleep medicine 39 Clinical psychology 40 Motor function rehabilitation 40 INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE) 41 Introduction by the Director 41 Research Units Experimental neuropathology 42 Experimental neurophysiology 42 Molecular genetics of behaviour 43 Neuromuscular repair 43 Neuroimmunology Unit 44 Clinical neuroimmunology 44 CNS repair 45 Neuroimaging research Unit 46 Neuroimaging of CNS white matter 46 Human inherited neuropathies Unit 46 Axo-glia interactions Unit 47 Clinical Research Units Inflammatory CNS disorders Unit 47 Cerebrovascular disorders 48 Memory disorders 49 Movement disorders 49 Neuromuscular disorders 49 Paroxysmal events 50 DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES 53 Introduction 56 Research Units Amino acid and stable isotopes Unit 57 Complications of diabetes 57 Obesity and metabolic related diseases 58 Bone metabolism Unit 58 Coagulation service & thrombosis research Unit 59 Cardiodiabetes & core lab 59 Pediatric endocrinology research 60 Clinical Research Units Diabetes and endocrinology Unit 60 Cardiodiabetes and clinical trials 61 Clinical pediatric endocrinology 61 Diabetes and metabolic diseases in children and adolescents 62 Neonatology 62 Foetal-maternal medicine 62 Infertility 63 Cardiovascular interventions Unit 63 Clinical cardiovascular biology Unit 64 Ischaemic heart disease, heart failure and echocardiography Unit 65 Organ protection in critically ill patients, advanced cardiac failure and mechanical supports Unit 65 Structural heart disease Unit 66 Study and treatment of aortic disease Unit 67 Center for arrhythmia research 67 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY 71 Introduction by the Directors 75 Research Units Skeletal muscle development and therapy Unit 76 Functional genetics of muscle regeneration 76 Gene expression and muscular dystrophy Unit 77 Molecular and functional immunogenetics 78 Neural stem cell biology 78 Autoimmunity & vascular inflammation Unit 79 Innate immunity and tissue remodelling 80 Cellular pharmacology Unit 80 Experimental hematology Unit 81 Angiogenesis and tumor targeting 81 Clinical Research Units Hematology and hematopoietic stem cell transplantation Unit 82 Immunohematology and transfusion medicine Unit 82 PSIEP - Strategic Program of Pediatric Immunohematology 83 THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE THERAPY (HSR-TIGET) 84 Introduction by the Director 84

6 INDEX - V Research Units Gene transfer technologies and new gene therapy strategies Unit 85 Gene/neural stem cell therapy for lysosomal storage diseases 85 Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders 86 Safety of gene therapy and insertional mutagenesis 86 Gene transfer into stem cells Unit 87 Immunological tolerance Unit 87 From FOXP3 mutation to IPEX syndrome 88 Tolerogenic dendritic cells 89 Pathogenesis and therapy of ADA-SCID Unit 89 Gene therapy for WASP/Omenn 90 Clinical Research Units Pediatric Clinical Research Unit - Gene therapy for Wiskott-Aldrich Syndrome 90 Pediatric Clinical Research Unit - ADA gene transfer into hematopoietic stem cells for the treatment of ADA-SCID 91 Pediatric Clinical Research Unit - Clinical trial of gene therapy in metachromatic leukodystrophy 92 DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES 95 Introduction by the Directors 100 Research Units Leukocyte biology Unit 101 Cellular and molecular allergology 102 Human virology 102 Infection and cystic fibrosis 103 Protein engineering and therapeutics 103 γδ T cells in innate and adaptive Immunity 104 Immunobiology of HIV 105 Immunological diagnostics of tuberculosis 105 AIDS immunopathogenesis Unit 106 Biocrystallography Unit 106 Cellular immunology Unit 107 Emerging bacterial pathogens Unit 107 Experimental immunology Unit 108 Immunopathology Unit 109 Lymphocyte activation Unit 109 Tumor immunology Unit 110 Viral evolution and transmission Unit 110 Viral pathogens and biosafety Unit 111 Clinical Research Units Neurovirology 111 Vaccine and Immunotherapy 112 Clinical immunopathology and advanced medical therapeutics Unit 112 Clinical transplant Unit 113 Gynecological cancers immunology 114 Immunology in liver neoplasms 114 Obesity 115 Pancreatic tumors: immunotherapy and β cell function substitution 115 Clinical hepato-gastroenterology 116 Digestive pathophysiology 116 Transplant surgery 116 DIABETES RESEARCH INSTITUTE (DRI) 117 Introduction by the Directors 117 Research Units Immune tolerance 118 Experimental diabetes 119 β cell biology 119 Cell imaging 120 Clinical Research Units Islet transplantation 121 Prevention in type 1 diabetes 122 Epidemiology & data management 122 Childhood diabetes 123 Islet processing activity 123 DIVISION OF GENETICS AND CELL BIOLOGY 127 Introduction by the Directors 130 Research Units Protein transport and secretion Unit 131 Age related diseases 131 Molecular immunology 132 Chromatin dynamics Unit 132 In vivo Chromatin and transcription 133 Biology of myelin Unit 134 Biomolecular mass spectrometry Unit 134 Gene expression Unit 135 Genetics of common disorders Unit 136 Molecular basis of polycystic kidney disease Unit 136 Molecular genetics Unit 137 Molecular dynamics of the nucleus 137 NeuroGlia Unit 138

7 VI - SAN RAFFAELE SCIENTIFIC INSTITUTE Regulation of iron metabolism Unit 139 Molecular genetics of renal disorders Unit 139 Clinical Research Units Dento-facial histopathology Unit 140 Genomics of renal diseases and hypertension Unit 141 Tissue engineering and biomaterials 141 CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS 145 Introduction by the Director 146 Research Units Neurogenomics Unit 147 Theoretical biology 147 Biogenesis and motility of secretory organelles Unit 148 Genomic Unit for the diagnosis of human pathologies 149 Proteome biochemistry Unit 149 Biomolecular NMR laboratory 150 FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications Laboratory 161 CERMAC, Centre of Excellence of High Field Magnetic Resonance 161 Mouse histopathology 162 THE CLINICAL DEPARTMENTS 165 Department of arrhythmology 166 Cardio-thoracic-vascular Department 167 Department of general and specialistic surgery 170 Head and neck Department 172 Department of infectious diseases 174 Maternal and child health Department 176 Department of internal and specialistic medicine 178 Department of clinical neuroscience 180 Department of neurology 182 Department of oncology 183 Department of radiology 185 Department of urology 187 CENTER FOR IMAGING 153 Introduction 154 Clinical Research Units Clinical and experimental radiology Unit 155 High technology in radiation therapy Unit 155 Molecular imaging Unit 156 Neuroradiology research group 157 FACILITIES 159 ALEMBIC, Advanced Light and Electron Microscopy Bioimaging Center 160 CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis 160 CLINICAL SERVICES 188 Medical physics 190 Pathology 190 Laboratory medicine 191 Service of immunohematology and transfusion medicine 191 Emergency medicine 192 General intensive care 192 Anaesthesia and neurointensive care Unit 193 PUBLICATIONS 195 Best papers List of 2008 publications 196

8 INTRODUCTIONS INTRODUCTIONS - VII

9

10 INTRODUCTIONS - IX Introduzione del Presidente Sono particolarmente felice di presentare anche quest anno il lavoro dei nostri ormai numerosi ricercatori. Sono convinto da sempre che non si può scegliere alcune linee di ricerca senza coltivare le molte altre. È perciò che mi sento soddisfatto di vedere ormai una piattaforma scientifica del San Raffaele di così vaste proporzioni. Una piattaforma che comprende in una unità strettamente organizzata e integrata la ricerca di base, la ricerca traslazionale, la ricerca clinica e applicata. È chiaro che su questa base io aspiro ad una continuità, anzi ad una intensificazione esplorativa in tutti i campi dello scibile e questo perché l Uomo: corpo, intelletto, spirito è una unità integrata, anche se le tre componenti sembrano essere tra loro molto diverse. Infatti, io credo che il rilancio del valore Uomo non può prescindere dalla unitarietà delle linee della di lui conoscenza, sia come σοµα (corpo), νουs (intelletto), ψυχη (anima, spirito). È questa la strada per farlo vivere sincrasicamente nell ambiente e nel tempo. Voglio anche aggiungere che l Uomo per venire lucidamente inteso va considerato per quello che egli è come sua genesi: l Uomo, cioè, non è un Ente in sé; è un Ente nell Ente essenzializzato, cioè nel Creatore Dio che all uomo ha comunicato per sinaptogenesi il suo potere di intelligere. Da ciò la imprescindibilità di una struttura come il San Raffaele tipo città dell Uomo dove le scienze, tutte le scienze, sono di casa, sono cioè a disposizione di tutti. Anche le Scienze umanistiche, la Metafisica e cioè la Ontologia, la Antropologia, la Teodicea ecc. e con tutte le altre conoscenze che fanno dell uomo: Uomo in progressione verticale. La nostra Identità Universitaria, cioè altamente culturale, dev essere per ogni suo componente il vero crocevia della cultura universale. È perciò che l Uomo non può far senza di quell Ente in sé che chiamiamo Dio e che si è rivelato nel Λογοs divino incarnandosi quale terminale facile all uomo per giungere direttamente a Dio. Cari ricercatori comprendete Voi tutto ciò? Per comprenderlo occorre sapere amare. Io, a novant anni, ci sono quasi arrivato e ho tentato di descriverlo plasticamente nel Vostro Ciborio e nella Vostra Cupola. Vostro Don Luigi Maria Verzé Presidente e Rettore

11 X - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the President I am particularly delighted to present this Annual Report of the scientific research work carried on by the numerous researchers operating in our University and Research Centers. I personally believe that it is impossible to choose a path of research while not following at the same time different others: a research is made out of different paths interweaved together. Thus, I cannot help but notice my satisfaction in observing such an important and great scientific platform as San Raffaele is. Such platform includes the basic research, the translational research and the clinic and applied researches into a joined unity. It is clear that I aspire to a continuity of research between all the different fields of knowledge which are to be interconnected on the basis that the human being body, mind and soul has to be considered an integrated unity. Even though the three elements which shape the human being are very different from each other, they compose a single blend. Indeed, I strongly believe that the importance and the value of the human being has to be raised in the unity of these three lines of knowledge, which pertain to the human being: the knowledge of the σοµα (body), the knowledge of the νουs (mind), the knowledge of the ψυχη (soul). This is the way necessary in order for the human being to live in space and time synchronously. I would like to add that to understand what the human being is, it is necessary to consider him for what he is in his/her genesis. In other words, the human being is not a being per se. On the contrary, the human being is a being in the Absolute being, created by God and to whom God transferred his power of knowledge by way of the synapses. As a consequence, the whole San Raffaele has to be shaped as a city of the Human being, where different fields of sciences, of all kinds of science, are to be welcomed, that is: they are to be available to everybody. Even those humanistic sciences, such as Metaphysics i.e. Ontology, Anthropology, Theodicy and so on are to be embraced together with those others which make the human being progressing forward, toward the highness. The identity of our University must be, to each of its members, the crossroad of the universal culture. For these reasons, the human being can neither act nor do anything without God, who revealed himself in the form of the divine Λογοs which can be easily grasped by each man and woman to arrive directly to God. Dear researchers, do you understand all that I am saying here? To understand it, it is necessary to have the capacity to love. I am ninety years old and I can say I have almost achieved such capacity and I have tried to described it physically to you with Your newly built Ciborio and Your Dome. Yours, Don Luigi Maria Verzé President and Chancellor

12 INTRODUCTIONS - XI Scientific Directorate SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo CHIEF OPERATING OFFICER: Maurizio Savi HEAD OF SCIENTIFIC OFFICE: Giulio Negri ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss GRANT OFFICE: Paola Rebagliati, Riccarda Daneri HEAD OF CLINICAL TRIAL OFFICE: Elisabetta Riva CLINICAL TRIAL OFFICE: Raffaella Biagetti, Giovanna Bombelli, Anna Negri, Giliola Calori, Margherita Ianniello, Maria Rosa Mandelli, Rossella Stefani Grazia Roncarolo HEAD OF BIOTECHNOLOGY TRANSFER OFFICE: Daniela Bellomo BIOTECHNOLOGY TRANSFER OFFICE: Lucia Faccio, Paola Pozzi, Roberto Santarella, Fabrizio Bacchi, Simona Locatelli HEAD OF LIBRARY: Laura Tei LIBRARY: Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati Maurizio Savi

13 XII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Scientific Director The mission of the San Raffaele del Monte Tabor Foundation is to conduct innovative research benefiting the care and cure of our patients and to provide state of the art education and training for new generations of doctors and scientists, with a high level of social responsibility. The San Raffaele Scientific Institute (SRSI) was one of the first private hospitals established in Italy in In 1972 it was granted by the Italian Ministry of Health the status of Research Hospital (IRCCS: Istituto di Ricovero e Cura a Carattere Scientifico ), with a main focus on diabetes and metabolic diseases. In 1992 a new research building ( sq m) was open to accommodate the Department of Biotechnology (DIBIT1). The initial areas of research covered by DIBIT1 were genetics, cell biology and immunology while in the late 90 s gene therapy, stem cell biology and molecular mechanisms of diseases were added. In recognition of its status as a center of excellence in Molecular Medicine, in 2001 the Italian Ministry of Health granted the SRSI the status of Molecular Medicine Research Institute. In 2006 the construction of a second ( sq m) research building (DIBIT2) was initiated to allow the much needed growth of the various SRSI research groups, to accommodate the new, centrally organized, state of the art technology platforms supporting our research activities and importantly, to expand our translational research efforts in key disease areas such as regenerative medicine, neuroscience, cardiovascular and oncology. The construction of DIBIT 2 progressed amazingly fast, and several Research Units moved already in. At present approximately 660 scientists and technicians are working in DIBIT1 and DIBIT 2, including postdoctoral fellows, PhD students and undergraduate students. Furthermore, 20 associates provide research services. In addition, 670 physicians work in clinical research projects (see also introduction by Maurizio Savi, chief operating officer for research). DIBIT1 and DIBIT2 are part of the San Raffaele Biomedical Science Park, which is the largest of its kind in Italy and includes the San Raffaele Hospital, with more than 1350 beds, and the Vita-Salute San Raffaele University, which was established in The University hosts the faculties of medicine, psychology and philosophy and provides specialized post graduate courses, resident programs in various medical specialties, and international PhD programs in Cellular/Molecular Biology and Molecular Medicine.

14 INTRODUCTIONS - XIII 2008 was a year of important chances for SRSI. A new redefined research strategy and organization have been designed and implemented to create optimal synergies between the different research areas, including clinical research, to prepare us for the future challenges and to increase our competitiveness in the international scientific arena. In this new strategic vision, research represents the backbone of our institution and the intersection that connects clinical and teaching activities. In this new model, research activities are consolidated in 6 Research Divisions whereas clinical activities are organized in 12 Clinical Departments (see also introduction by Renato Botti, general director of clinical area). The Research Divisions are crossing many Clinical Departments in a matrix model, in which research units and clinical units are fully integrated. In addition, 3 specialized Research Core and Centers have been established to meet the increasing need for state of the art imaging technologies, molecular pathology, functional genomics, proteomics and bioinformatics. Research at the SRSI covers many disciplines, which include genetics, cell biology, stem cell biology, gene therapy, immunology, and focuses on several diseases, which include cancer, transplant rejection, autoimmunity and infections, neurodegenerative, cardiovascular and metabolic diseases. Research conducted in these areas has the common goal to advance knowledge about molecular basis of diseases and to identify innovative therapies and new diagnostic options. The 6 Research Divisions and 3 Research Cores (see list at page XXIV) approved by the Board and implemented in 2008 represent existing areas of expertise and excellence as well as new strategic area of research in which we want to invest for the future according to our strategic plan. Within this new divisional organization, 3 major research Institutes continue to operate: the San Raffaele Telethon Institute for Gene Therapy of Genetic Diseases (HSR-TIGET), which is pioneering gene therapy to cure patients with monogenic diseases, the Institute for Experimental Neurology (INSPE), which investigates the biological and molecular mechanisms underlying diseases of the nervous system with a strong focus on clinical translation, and the recently established Diabetes Research Institute (HSR-DRI) whose main objective is to identify and apply novel treatments to prevent islet beta cell destruction and to restore sufficient insulin production in type 1 diabetes. Furthermore, the SRSI hosts several scientists belonging to the Dulbecco-Telethon Institute (DTI) working on molecular and biological mechanisms of gene regulation and genetic diseases. In 2008 we also defined the areas in which interdivisional and interdepartmental research programs have to be consolidated or implemented. The research Divisions are led by the Directors, appointed for three years and nominated by the President of the Board of Directors, with the approval of the President of the Board of Director of the University Vita-Salute San Raffaele. A Scientific and Technical Committee has also been appointed to support the scientific and operating directors in the strategic research planning and in the definition of new initiatives. In parallel to the implementation of this new research structure, the administrative and supporting research structure was also extensively reorganized with the hiring of the Chief Operating Officer for research (see introduction by Maurizio Savi). In this new organization, the administrative office, the research development and quality control office, the grant office, the library, the office of biotechnology transfer and the office for clinical experimentation are under the direct responsibility of the scientific and operating directors has been another very productive year for the SRSI. The high productivity and quality of our research in 2008 is reflected by the total number and the total impact factor of our publications, with a remarkable number of manuscripts published in top level scientific journals, as illustrated in figures 1 and 2: Publications and total Impact Factor Publications distributed in Impact Factor ranges 100% 3785, , , Percentage of publications 80% 60% 40% 20% 65% 63% 62% 26% 28% 30% 9% 10% 8% 2006 (average IF: 5,265) 2007 (average IF: 5,139) 2008 (average IF: 5,230) 0% < Impact Factor ranges Total IF Publications

15 XIV - SAN RAFFAELE SCIENTIFIC INSTITUTE Furthermore, the close links and synergy between the Research Institute and the Hospital is documented by the number and quality of our clinical trials, with around two hundreds clinical trials evaluated and approved by our Ethical Committee and a significant proportion of investigator initiated trials in several therapeutic area, as illustrated in the figures below: Clinical trials evaluated by the HSR Ethical Committee in 2008 Pharmaceutical companies sponsored trials No-profit groups sponsored trials HSR investigators initiated trials Pharmacological protocols Basic research protocols Observational procotols Medical device protocols 28% 50% 25% 1% 55% 22% 19% Clinical trials approved in 2008 by therapeutic area Infectious diseases Oncology/Hematology Neurology Diabetology Cardiology/Arrhythmology Urology Ophthalmology Anaesthesiology and intensive care Sponsored trials No-profit trials 11% 1% 8% 7% 1% 18% 5% 3% 11% 5% 8% 35% 19% 35% 14% 19% The competitiveness of the SRSI is also demonstrated by its ability to attract funding not only from public (Ministry of Health, Superior Institute of Health, Ministry of University and Research) but also from private Italian sources (mainly Telethon, the Italian Association for Cancer Research and Bank Foundations) and from international sources (e.g. European Community, European Research Council, American National Institute of Health, World Health Organization, Association for International Cancer Research, Gates Foundation, Wellcome Trust, Juvenile Diabetes Research Foundation). Finally, SRSI is an attractive partner for big pharmaceutical and biotechnology companies, as it is reflected by the many collaborations with our scientists which were supported by the office of biotechnology transfer which has the mission to create value from the intellectual property and know-how of the SRSI and Hospital. These achievements have been made possible by the excellence of our scientists and clinicians, as also documented by the prestigious international awards won in In addition, the strong sense of community and the synergy and cooperation between different teams were highlighted by our yearly Scientific Retreat where basic and clinical scientists were brought together to discuss scientific progress and future plans. Finally, in 2008 a number of important educational initiatives, scientific events and prestigious international meetings have been organized and hosted by our basic and clinical scientists.

16 INTRODUCTIONS - XV LOOKING FORWARD We are very much looking forward to occupy the new buildings and to use the new space to consolidate the research divisions, to build state of the art technology platforms and to enter into new research areas. SRSI will continue to be a multidisciplinary Institute, but we will also pay particular attention to invest into research in diseases with a high unmet medical need and into therapeutic areas of increasing medical demand such as oncology. We will continue to strengthen our position as a leading center for translational medicine with strong links to high quality clinical research. In this context, close collaborations between basic (fundamental) researchers, clinical investigators and physician scientists will be strongly solicited and favored with the ultimate goal to apply new therapeutic principles, invented at the laboratory benches, as efficiently as possible to our patients. We will continue to build expertise in the field of molecular and experimental medicine, including wide genome analysis of complex diseases, stratification of patients by genotyping and phenotyping, farmacogenetics and farmacogenomics. We will implement a competitive postdoctoral program to attract international young scientists and foster international exchanges. In addition, we will establish a career path for physician scientists and young investigators. I am confident that this research strategy and structure will further enhance SRSI s position as an Institute of excellence conducting innovative science in the field of Molecular Medicine, which at the end benefit our patients. In the coming future this strategy and structure will be presented to our internationally renowned scientific advisory board which will not only give us valuable suggestions but play a particular important role as we establish high research standards. The worldwide financial and economical crisis that looms over all of us as we write this scientific report threatens the implementation of our new strategic research plan and organization. However, the unconditioned support of our President, as well as the trust of our Board, the motivation of our research directors and the enthusiasm of our scientists and clinical researchers help us to be optimistic and confident that SRSI will continue to grow and operate at the leading edge of biomedical research. In addition, the moral obligation and responsibility we have towards the younger generations of scientists and physicians to create an environment where they will be allowed to grow and to build their careers gives us strength and determination. I like to express my gratitude to the scientists, physicians, staff, post-doctoral fellows and students that with their work, effort, enthusiasm and passion contributed to the research progress illustrated in this 2008 scientific report. I hope you will find our report interesting and inspiring. Maria Grazia Roncarolo Scientific director

17 XVI - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Chief Operating Officer The San Raffaele Scientific Institute s biomedical research covers several areas, all closely related to the theme of Molecular Medicine, which brings together basic research, clinical research and healthcare with the common goal of transferring preclinical research to the bedside and of translating scientific findings into innovative therapies. With this global strategic vision, the San Raffaele Scientific Institute strives to enhance its position as a Center of Excellence in Molecular Medicine by strengthening its infrastructure and redrawing its organization. The new organization is the result of a project started in 2008 and it is based on a macro-structure processes model, which aims at: 1. Creating a common scientific direction inside the Opera, which inspires and supports the San Raffaele Scientific Institute. 2. Guaranteeing a complete integration between the main three areas of activities: scientific research, health and education. 3. Ensuring the sustainability of the Research Area on the basis of efficacy, efficiency and economy criteria. 4. Creating an infrastructure and organization based on the individual value by promoting professional valorization and establishing a working environment where people are able to develop and express competences and expertise in the best way. In order to reach these goals we have: Identified the criteria and the rules for the establishment and functioning of the Research Divisions and Research Cores. Defined the modalities to implement efficient and valid guidelines for the organization of both scientific and administrative activities, establishing clear levels of managerial, administrative and technical responsibilities. Ensured an efficient communication system and a flow of information continuously and efficiently open to all users. The San Raffaele Scientific Institute firmly believes in the value of communication and, since 2008, it has strengthened its Marketing and Fund Raising Staff with the aim to improve the general knowledge on its activities, results and projects by using the main communication media, but also with the goal to better support its funding possibilities by potentiating the relationships with the main National and International funding agencies for scientific research. FOCUS ON SOME NUMBERS RESEARCH - TOTAL REVENUES YEAR 2008 OTHER REVENUES -YEAR 2008 RESEARCH INCOME - YEAR 2008 OTHER REVENUES; 10,86% RESEARCH INCOME; 89,14% EXTERNAL SERVICES; 10,45% OTHER INCOME; 13,58% INTERNAL SERVICES; 37,38% DONATIONS; 38,59% EXTERNAL GRANTS; 43,78% SPONSORED RESEARCH; 4,48% CLINICAL TRIALS; 7,84% PUBLIC FUNDS; 43,91% DONATIONS INTERNAL SERVICES EXTERNAL SERVICES OTHER INCOME RESEARCH INCOME OTHER REVENUES SPONSORED RESEARCH CLINICAL TRIALS PUBLIC FUNDS EXTERNAL GRANTS

18 INTRODUCTIONS - XVII BUILDING UP THE FUTURE At the end of this year the new construction called Dibit2 will be completed and equipped. These buildings represent the hearth of the scientific long term vision of our Institute. The construction consists of three buildings: In the center there is the Basilica building, which, as its name suggests (taken from the Greek culture), represents a space where people can meet, interact, and discuss to advance scientific knowledge and promote scientific culture. In this block there are the Faculty of Medicine and Surgery and the Faculty of Psychological Sciences. Furthermore the advanced technological research based on DNA discovery and function will be conducted in this building by the Genetic and Cell Biology Research Division and the Research Center for Genomics, Bioinformatics and Biostatistics. The Research Center for Imaging and an Open Lab conceived as a common area for the Research Divisions and the Clinical Groups will also be located in this area. On each side of the Basilica there are two buildings. The first building is occupied by the Neurosciences Research Division and the Diagnostic Division; whereas the Research Division of Regenerative Medicine, Stem Cells and Gene Therapy and the Research Division of Molecular Oncology will move into the second building. The Research Division of Immunology, Transplantation and Infectious Diseases and the Metabolic and Cardiovascular Disease Division will maintain their actual location in Dibit1. The total space dedicated to the research activity at San Raffaele will cover about square meters with about operators: 660 for Basic Research Units, 670 for Clinical Research Groups and 20 for Facilities. Maurizio Savi Chief Operating Officer

19 XVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE SAN RAFFAELE SCIENTIFIC RETREAT 2008

20 INTRODUCTIONS - XIX

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